Shuhendler Adam J, Pu Kanyi, Cui Lina, Uetrecht Jack P, Rao Jianghong
1] Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, California, USA. [2].
Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, California, USA.
Nat Biotechnol. 2014 Apr;32(4):373-80. doi: 10.1038/nbt.2838. Epub 2014 Mar 23.
Current drug-safety assays for hepatotoxicity rely on biomarkers with low predictive power. The production of radical species, specifically reactive oxygen species (ROS) and reactive nitrogen species (RNS), has been proposed as an early unifying event linking the bioactivation of drugs to hepatotoxicity and as a more direct and mechanistic indicator of hepatotoxic potential. Here we present a nanosensor for rapid, real-time in vivo imaging of drug-induced ROS and RNS for direct evaluation of acute hepatotoxicity. By combining fluorescence resonance energy transfer (FRET) and chemiluminescence resonance energy transfer (CRET), our semiconducting polymer-based nanosensor simultaneously and differentially detects RNS and ROS using two optically independent channels. We imaged drug-induced hepatotoxicity and its remediation longitudinally in mice after systemic challenge with acetaminophen or isoniazid. We detected dose-dependent ROS and RNS activity in the liver within minutes of drug challenge, which preceded histological changes, protein nitration and DNA double-strand-break induction.
当前用于肝毒性的药物安全性检测依赖于预测能力较低的生物标志物。自由基的产生，特别是活性氧（ROS）和活性氮（RNS），已被认为是将药物生物活化与肝毒性联系起来的早期统一事件，也是肝毒性潜力更直接的机制指标。在此，我们展示了一种纳米传感器，用于对药物诱导的ROS和RNS进行快速、实时的体内成像，以直接评估急性肝毒性。通过结合荧光共振能量转移（FRET）和化学发光共振能量转移（CRET），我们基于半导体聚合物的纳米传感器使用两个光学独立通道同时并分别检测RNS和ROS。在用对乙酰氨基酚或异烟肼进行全身攻击后，我们对小鼠体内药物诱导的肝毒性及其修复过程进行了纵向成像。在药物攻击后几分钟内，我们在肝脏中检测到剂量依赖性的ROS和RNS活性，这先于组织学变化、蛋白质硝化和DNA双链断裂诱导。
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